Differences in the level of exposure to traditional risk factors do not explain the observation that some patients with atherosclerosis primarily manifest it in the coronary arteries, whereas others manifest the disease in peripheral arteries. Because known systemic risk factors and environmental influences are similar in patients with coronary artery disease (CAD) and those with peripheral arterial disease (PAD), unknown environmental and genetic factors may be responsible for the individual heterogeneity in plaque distribution. Accordingly, the specific aims of this proposal are to elucidate genetic determinants which influence the propensity to develop hemodynamically significant atherosclerosis in the coronary or peripheral arteries; to identify genetic determinants which preferentially influence the susceptibility to PAD; and to examine the interaction of these genetic determinants with known risk factors for atherosclerosis. This is a cross-sectional case-control genomic study of two sharply defined clinical phenotypes. Cases will have hemodynamically significant PAD as documented by reduced ankle-brachial indices (ABIs). Controls will have similar clinical co-variants (i.e. similar risk factor profile) but will not have significant PAD as documented by normal ABIs. Genomic DNA will be isolated and SNPs detected using high throughput Taqman analysis. Data will be gathered on other clinical covariates (e.g. blood pressure, tobacco exposure, family history, and plasma levels of lipoproteins, glucose, homocyst(e)ine, C-reactive protein). The inclusion of both clinical and genetic data as risk predictors will allow us to identify the unique contribution of the new genetic polymorphisms. We will focus on single nucleotide polymorphisms (SNPs) in candidate genes that are regulated in the vasculature. SNPs will be chosen based on their prevalence, their location, and their effect on the primary amino acid sequence of the protein. The candidate genes targeted for study will be selected based upon our prior and ongoing work which focuses upon transcriptional profiling of vascular cells exposed to pathophysiologically relevant stimuli, with in vivo confirmation. This work links a multidisciplinary group at Mt. Sinai and Stanford University which has extensive expertise in cell and vascular biological studies, integrative physiology, human genomic and genetic studies, epidemiology and clinical trials in PAD.